Role of hydrophilic interaction in binding of hydroxylated 3-deoxy C-19 steroids to the active site of aromatase

As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, C-19 steroids having no oxygen functio n at C-3, we tested aromatase inhibition activity of polar diol compounds 4 ,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-e n-17-ones (36 and 37). 4 alpha ,19-Diol 25 was synthesized from tert-butyld imethylsily-oxyandrost-4-ene steroid (9) through its OsO4 oxidation, giving the 4 alpha ,5 alpha -dihydroxy derivative 12, as a key reaction. Acetylat ion of 5 beta ,6 alpha -dihydroxy-19-acetate 30 and its 5 alpha ,6 beta -an alogue 31 followed by dehydration with SOCl2 and alkaline hydroxysis gave 6 alpha ,19-diol 36 and its 6 beta -isomer 37, respectively. The stereochemi stry of a hydroxy group at C-4 of compound 25 and that at C-6 of compounds 36 and 37 were determined on the basis of H-1 NMR spectroscopy in each case . 4 beta ,19-Diol 27, previously synthesized, was identified as an extremel y powerful competitive inhibitor of aromatase (K-i = 3.4 nM). In contrast, its 4 alpha ,19-dihydroxy isomer 25 and other series of diol compounds, 6,1 9-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibit ors (K-i = 110-800 nM). Through this series of analyses, it was concluded t hat hydrophilic interaction of a 4 beta ,19-diol function with the active s ite of aromatase plays a critical role in the tight binding of 3-deoxy-5-en e steroids.